Penn Human Pancreas Analysis Program ? T2D Abstract Building on our existing infrastructure and scientific collaborations, and the expertise gained during the first two years of the HPAP effort for Type 1 Diabetes, we have assembled five cores with expertise ranging from pancreas procurement and islet isolation to data integration. These Cores form a for a comprehensive and integrated Penn Human Pancreas Analysis Program ? T2D based entirely at the University of Pennsylvania. Core A will procure a spectrum of human pancreata and detailed donor medical history; perform high resolution HLA typing by next generation sequencing; isolate islets; and distribute islets and tissues to the other Cores for further analysis or processing. Core B will perform physiological phenotyping on the isolated islets. Core C will perform multiple advanced modalities for the molecular profiling of isolated islets including RNAseq, ATACseq and DNA methylome analysis of sorted islet cell populations; single cell ATACseq and RNAseq, and mass cytometry for single cell quantification of more than 20 cell surface and intracellular markers. Core D will process tissues using multiple modalities that will allow for analysis using advanced technologies such as multiplexed immunoflourescent staining, whole slide imaging, and imaging mass cytometry. This Core will also archive tissues, DNA and blood, as well as other T2D-relevant organs such as skeletal muscle, intestine, adipose tissue and liver for future use by other NIDDK-approved consortia. Finally, Core E will assemble, annotate and maintain an open-access database for the Program and its member-researchers, and collaborate with the HIRN in the sharing of data from both programs. The entire program will directed by an Executive Committee consisting of the core leaders and the PI, who will be the interface with HIRN and NIDDK leadership. HPAP-T2D will provide physiologic, genomic, genetic, and histological analysis of the pancreas in type 2 diabetes at unprecedented detail, share the rich data with researchers world-wide before publication, and thus enable breakthrough discoveries in our understanding of this disease that has reached epidemic levels world-wide.